EP0126813A1 - Process for preparing imidazole compounds - Google Patents

Process for preparing imidazole compounds Download PDF

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EP0126813A1
EP0126813A1 EP83302986A EP83302986A EP0126813A1 EP 0126813 A1 EP0126813 A1 EP 0126813A1 EP 83302986 A EP83302986 A EP 83302986A EP 83302986 A EP83302986 A EP 83302986A EP 0126813 A1 EP0126813 A1 EP 0126813A1
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compound
formula
erythro
preparing
npt
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EP0126813B1 (en
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Lionel Norton Simon
Hans-Rudolf Mueller
Hans Zutter
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Newport Pharmaceuticals International Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • C—CHEMISTRY; METALLURGY
    • C05—FERTILISERS; MANUFACTURE THEREOF
    • C05D—INORGANIC FERTILISERS NOT COVERED BY SUBCLASSES C05B, C05C; FERTILISERS PRODUCING CARBON DIOXIDE
    • C05D9/00—Other inorganic fertilisers
    • C05D9/02—Other inorganic fertilisers containing trace elements
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4

Definitions

  • R is lower alkyl, e.g. of 1 to 4 carbon atoms such as methyl, ethyl, propyl, or butyl or halogen of atomic weight 35 to 80, i.e. chlorine or bromine.
  • NPT 15459 The compound erythro-3-(2-hydroxy-3-nonyl)-4-amino-imidazole-5-carboxamide (NPT 15459) is useful in producing NPT 15392 and its homologues of formula (1) above are useful in making the corresponding homologues of NPT 15392.
  • NPT 15459 and its homologues are useful in preparing novel analogues of NPT 15392 (and its homologues which contain various functional groups in the 2-position of the purine ring, e.g. the compounds of formulae (2) and (3). Such derivatives would be difficult to prepare without the aid of NPT 15359 and its homologues.
  • the compounds of formulae (1), (2), and (3) also have immunomodulating or immunopotentiating activity.
  • An immunopotentiator or immunomodulator is any agent which either restores depressed immune function, or enhances normal immune function, or both.
  • Immune function is defined as the development and expression of humoral (antibody-mediated) immunity, cellular (thymocyte-mediated) immunity, or macrophage and granulocyte mediated resistance. It logically includes agents acting directly on the cells involved in the expression of immune response, or on cellular or molecular mechanisms which, in turn, act to modify the function of cells involved in immune response. Augmentation of immune function may result from the action of an agent to abrogate suppressive mechanisms derived by negative-feedback influences endogenous or exogenous to the immune system.
  • immune potentiators have diverse mechanisms of action. Despite the diversity of cell site of action and biochemical mechanism of action of immunopotentiators, their applications are essentially the same; that is, to enhance host resistance.
  • Each of the protective functions of the immune system can be modified by non-specific therapy with immunopotentiators alone or in combination with other agents employed to improve resistance or to kill the invading pathogen.
  • specific resistance can be augmented by use of immunopotentiators in conjunction with some form of antigen as in a vaccine employing, for example, virus, tumor cells, etc. This use can be to induce either specific immunity or tolerance.
  • the latter might be exemplified by use with antigen in allergy or auto-immune diseases.
  • Use of immunopotentiators may be either therapeutic or prophylactic; the latter particularly in aging, where infection, auto-immunity, and cancer are more common.
  • the timing of administration and routes are variable and may be critical in determining whether a positive or negative response results. Any agent capable of augmenting immune response may inhibit it depending on timing and dose; thus, under certain circumstances an immunopotentiator could be used as an immunosuppressive agent for use in allergy, auto-immunity and transplantation.
  • NPT 15459 Illustrative of compounds within the invention in addition to NPT 15459 are:
  • NPT 15459 The synthesis of NPT 15459 is carried out according to the scheme presented below:
  • the other compounds within formula (1) can be prepared in the same manner by replacing erythro-3-amino-2-nonanol by the corresponding aminoalcohol, e.g. erythro-3-amino-2-pentanol and erythro-3-amino-2-octanol.
  • erythro-3-amino-2-pentanol e.g. erythro-3-amino-2-pentanol
  • erythro-3-amino-2-octanol erythro-3-amino-2-octanol.
  • ethyl orthoformate there can be used other lower alkyl orthoformates, e.g. methyl orthoformate, propyl orthoformate and butyl orthoformate.
  • the homologues of NPT 15392 can be prepared in the same manner from the corresponding homologues of NPT 15459.
  • ethyl orthoformate there can be employed the other lower alkyl orthoformates, e.g. the methyl, propyl, and butyl orthoformates.
  • the acetic anhydride forms the acetate of NPT 15392 and this is then hydrolized with alkali, e.g. sodium hydroxide.
  • the reaction mixture is concentrated to a viscous syrup, which is stirred into a mixture of 415 ml of 30% aqueous NaOH and 1.68 liter of water.
  • the brown solution is slightly acidified by addition of a solution of 123 ml of acetic acid in 1.5 liter of water.
  • Erythro-9-(2-hydroxy-3-nonyl)-hypoxanthine (VI) crystallizes, is filtered by suction, washed with water and dried in vacuo at 60°C. Yield: 350 g corresponding to 81.4% of theory
  • Melting point (after repeated recrystallization from aqueous ethanol): 200-201°C Content by titration: 99.4% Content of threo isomer: 0.9%
  • NPT 15459 and its homologues possess the ability to react with a variety of reagents which could lead to ring closure and the production of novel purine derivatives.
  • reagents which could lead to ring closure and the production of novel purine derivatives.
  • 2-substituted derivatives of NPT 15392 and its homologues that could not be produced by other means.
  • the scheme provided in the following diagram illustrates a number of such examples. erythro-2-amino-g-(2-hydroxy-3-nouyl)-hypoxuathine
  • R 1 is the group
  • the 2,6-dichloro-purine compound in the above scheme can be converted to the 2-chloro hypoxanthine using conventional procedures, e.g. by refluxing with sodium hydroxide in the manner shown in Simon U.S. patent 4,221,909 Method D.
  • the latter compound can then be converted to the corresponding 2-amino-hypoxanthine by reacting with methanolic ammonia in a manner analogous to that shown in Simon U.S. patent 4,221,909 Method B.
  • Compounds of formula (3) where R is methyl can be made by reacting NPT 15459 or its homologues with ethyl orthcacetate rather than ethyl orthoformate.
  • Compounds of formula (3) where R is ethyl can be made in similar manner by reacting NPT 15459 with ethyl orthopropionate.
  • the compounds of the present invention can be fed to a mammal at a dosage of 1-1000 mg/kg of body weight and could be anticipated to be active at levels as low as 0.0005 mg/kg.
  • Aqueous suspensions can be made with a number of suspending agents incorporated with the active drug substances. Included as suspending agents are such substances as sodium carboxymethylcellulose, Na alginate gum, tragacanth, Avicel RC-591 (microcellulose), methylcellulose, Veegum, Xanthan gum. In addition to a suspending agent such substances as sweetners, flavors, colorants, preservatives, protective colloids, and dispersants may be added.

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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Pest Control & Pesticides (AREA)
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  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

There are prepared compounds of the formulae
Figure imga0001
Figure imga0002
 where R is a lower alkyl, chlorine, or bromine and n is an integer from 1 to 5. The compounds of formula (1) can be used to make erythro-9-(2-hydroxy-3-nonyl) hypoxanthine and its homologues and also to make the compounds of formulae (2) and (3). All three classes of compounds are useful as immunomodulators.

Description

    BACKGROUND OF THE INVENTION
  • Simon U.S. patents 4,221,909 and 4,211,794 and Giner-Sorolla U.S. patent 4,221,910 and Faanes International Journal of Immunopharmacology, Vol. 2, No. 3, page 197 (1980), Florentine, International Journal of Immunpharmacology, Vol. 2, No. 3, page 240 (1980), Hadden, International Journal of Immunopharmacology, Vol. 2, No. 3, page 198 (1980), Pahwa, International Journal of Immunopharmacology, Vol. 2, No. 3, page 199 (1980), Wybran, International Journal of Immunopharmacology, Vol. 2, No. 3, page 201 (1980) and Simon, 4th International Congress of Immunology, Paris (1980) show that erythro-9-(2- hydrcxy-3-nonyl)-hypoxanthine (NPT 15392), as well as other members of the series described in the patents cited above are potent immunomodulating agents which have been demonstrated to enhance depressed immunity in both animals possessing tumors, Sato, International Journal of Immunopharmacology, Vol. 2, No. 3, page 200 (1980), as well as in humans with various tumors, Simon, American Chemical Society Book of Abstracts, 182nd American Chemical Society Meeting (1981). While the synthesis of these therapeutically useful agents can be carried out by the methods described in the patents cited above, their production, e.g. the production of NPT 15392, on a large scale using those methods was cumbersome, costly, and time consuming.
    • SUMMARY OF THE INVENTION
  • There are prepared compounds of the formulae
    Figure imgb0001
    Figure imgb0002
    Figure imgb0003
     where R is lower alkyl, e.g. of 1 to 4 carbon atoms such as methyl, ethyl, propyl, or butyl or halogen of atomic weight 35 to 80, i.e. chlorine or bromine.
  • The compound erythro-3-(2-hydroxy-3-nonyl)-4-amino-imidazole-5-carboxamide (NPT 15459) is useful in producing NPT 15392 and its homologues of formula (1) above are useful in making the corresponding homologues of NPT 15392. In addition to being useful in making NPT 15392 and its homologues, NPT 15459 and its homologues are useful in preparing novel analogues of NPT 15392 (and its homologues which contain various functional groups in the 2-position of the purine ring, e.g. the compounds of formulae (2) and (3). Such derivatives would be difficult to prepare without the aid of NPT 15359 and its homologues.
  • The compounds of formulae (1), (2), and (3) also have immunomodulating or immunopotentiating activity.
  • An immunopotentiator or immunomodulator is any agent which either restores depressed immune function, or enhances normal immune function, or both. Immune function is defined as the development and expression of humoral (antibody-mediated) immunity, cellular (thymocyte-mediated) immunity, or macrophage and granulocyte mediated resistance. It logically includes agents acting directly on the cells involved in the expression of immune response, or on cellular or molecular mechanisms which, in turn, act to modify the function of cells involved in immune response. Augmentation of immune function may result from the action of an agent to abrogate suppressive mechanisms derived by negative-feedback influences endogenous or exogenous to the immune system. Thus, immune potentiators have diverse mechanisms of action. Despite the diversity of cell site of action and biochemical mechanism of action of immunopotentiators, their applications are essentially the same; that is, to enhance host resistance.
    • Applications of Immunopotentiators
    • 1) The principal protective function of the immune system relates to resistance to invasion by pathogens, including viruses, rickettsia, myco- plasma, bacteria, fungi, and parasites of all types. Thus, improvement of immune response, particularly when depressed, would calculatedly improve resistance in infection or infestation by any of the above pathogens. An immunopotentiator alone or in combination with anti-infective therapy can be applied to any and all infectious diseases.
    • 2) A second protective function of the immune system is thought to be resistance to engraftment of foreign tissue, either natural as in the fetal-maternal relationship; or unnatural as performed by the transplant physician. Immunopotentiators can also be used to facilitate rejection of fetal or placental tissues or to modify or induce tolerance to grafts.
    • 3) A third protective function of the immune system is thought to be resistance to malignant cell development as in cancer. The use of immunopotentiators can be used in cancer treatment to enhance tumor rejection and to inhibit tumor recurrences followling other forms of therapy.
    • 4) A fourth protective function involves the capacity to recognize foreignness and to maintain nonreactivity to self by positive suppressor mechanisms. In auto-immune and related disorders, immune reactivity directed at self antigens or exaggerated, elevated responses are apparent which are self-destructive. Immunopotentiators can be used to restore normal suppressor mechanisms, induce tolerance, or otherwise promote a normal immune response.
  • Each of the protective functions of the immune system can be modified by non-specific therapy with immunopotentiators alone or in combination with other agents employed to improve resistance or to kill the invading pathogen. In addition, specific resistance can be augmented by use of immunopotentiators in conjunction with some form of antigen as in a vaccine employing, for example, virus, tumor cells, etc. This use can be to induce either specific immunity or tolerance. The latter might be exemplified by use with antigen in allergy or auto-immune diseases. Use of immunopotentiators may be either therapeutic or prophylactic; the latter particularly in aging, where infection, auto-immunity, and cancer are more common. The timing of administration and routes are variable and may be critical in determining whether a positive or negative response results. Any agent capable of augmenting immune response may inhibit it depending on timing and dose; thus, under certain circumstances an immunopotentiator could be used as an immunosuppressive agent for use in allergy, auto-immunity and transplantation.
  • Various procedures for determining immunomodulating activity are shown in Simon E.P.O. published application 0036077,
  • Illustrative of compounds within the invention in addition to NPT 15459 are:
    • erythro-3-(2-hydroxy-3-amyl)-4-amino- imidazole-5-carboxamide,
    • erythro-3-(2-hydroxy-3-hexyl)-4-amino- imidazole-5-carboxamide,
    • erythro-3-(2-hydroxy-3-heptyl)-4-amino- imidazole-5-carbozamide,
    • erythro-3-(2-hydroxy-3-octyl)-4-amino- imidazole-5-carboxamide,
    • erythro-9-(2-hydroxy-3-nonyl)-2-amino-hypoxanthine,
    • erythro-9-(2-hydroxy-3-amyl)-2-amino-hypoxanthine,
    • erythro-9-(2-hydroxy-3-hexyl)-2-amino-hypoxanthine,
    • erythro-9-(2-hydroxy-3-heptyl)-2-amino-hypoxanthine,
    • erythro-9-(2-hydroxy-3-octyl)-2-amino-hypoxanthine,
    • erythro-9-(2-hydroxy-3-nonyl)-2-chloro- hypoxanthine,
    • erythro-9-(2-hydroxy-3-amyl)-2-chloro- hypoxanthine,
    • erythro-9-(2-hydroxy-3-hexyly-2-chloro- hypoxanthine,
    • erythro-9-(2-hydroxy-3-heptyl)-2-chloro- hypoxanthine,
    • erythro-9-(2-hydroxy-3-octyl)-2-chloro- hypoxanthine,
    • erythro-9-(2-hydroxy-3-nonyl)-2-bromo- .hypoxanthine, erythro-9-(2-hydroxy-3-amyl)-2-bromo- hypoxanthine,
    • erythro-9-(2-hydroxy-3-nonyl)-2-methyl- hypoxanthine, erythro-9-(2-hydroxy-3-amyl)-2-methyl- hypoxanthine,
    • erythro-9-(2-hydroxy-3-hexyl)-2-methyl- hypoxanthine,
    • erythro-9-(2-hydroxy-3-heptyl)-2-methyl- hypoxanthine,
    • erythro-9-(2-hydroxy-3-octyl)-2-methyl- hypoxanthine,
    • - erythro-9-(2-hydroxy-3-nonyl)-2-ethyl- hypoxanthine,
    • erythro-9-(2-hydorxy-3-hexyl)-2-ethyl- hypoxanthine, and
    • erythro-9-(2-hydroxy-3-amyl)-2-ethyl- hypoxanthine.
    BRIEF DESCRIPTION OF THE DRAWINGS
    • Figure 1 is the IR-spectrum of NPT 15459, and
    • Figure 2 is the UV-spectrum of NPT 15459.
    DETAILED DESCRIPTION
  • The synthesis of NPT 15459 is carried out according to the scheme presented below:
    Figure imgb0004
    Figure imgb0005
  • The other compounds within formula (1) can be prepared in the same manner by replacing erythro-3-amino-2-nonanol by the corresponding aminoalcohol, e.g. erythro-3-amino-2-pentanol and erythro-3-amino-2-octanol. In place of ethyl orthoformate there can be used other lower alkyl orthoformates, e.g. methyl orthoformate, propyl orthoformate and butyl orthoformate.
    • Example 1 Synthesis of Erythro-3-(2-hydroxy-3-nonyl)-4-amino-imidazole-5-carboxamide (NPT 95459 (V))
  • For improved yield, reactions (1) and (2) above are carried out sequentially without isolation of the intermediate product III. 2-amino-2-cyano- acetamide (1) (171 g, 1.71 moles) is suspended in 2200 ml of acetonitrile. Orthoformic acid triethylester (II) (334 ml - 2.0 moles) and 2 ml of pyridine are added to the suspension with stirring. The suspension is heated to reflux temperature, using an oil bath preheated to 100°C. The suspension is held at boiling temperature for 40 to 60 minutes. III is produced in situ. 272.5 g of erythro-3-amino-2-nonanol (IV) (1.71 moles) are then added over a 3 to 5 minute period and boiling is continued for an additional 10 to 15 minutes. The reaction is quickly chilled to room temperature. The erythro-3-(2-hydroxy-3-nonyl)-4-amino-imidazole-5-carboxamide (NPT 15459) (V) crystallizes. It is filtered by suction, washed with a small amount of acetonitrile and dried in vacuo at 70°C.
  • Yield: 330.4 g, 72% of theory Melting point (after recrystallization from acetonitrile): 154-158°C.
  • SUMMARY OF CHEMICAL PROPERTIES OF (NPT 15459)
    Figure imgb0006
  • Identity
    Figure imgb0007
    • UTILIZATION OF NPT 15459 TO PRODUCE NPT 15392
  • The reaction scheme described below illustrates the use of NPT 15459 in the synthesis of NPT 15352:
    • Reaction Scheme:
      Figure imgb0008
  • The homologues of NPT 15392 can be prepared in the same manner from the corresponding homologues of NPT 15459. In place of ethyl orthoformate there can be employed the other lower alkyl orthoformates, e.g. the methyl, propyl, and butyl orthoformates. In forming NPT 15392 the acetic anhydride forms the acetate of NPT 15392 and this is then hydrolized with alkali, e.g. sodium hydroxide.
  • In place of an orthoformic acid ester formic acid can also be used.
    • Example 2 UTILIZATION OF NPT 15459 TO PRODUCE NPT 15392. (Erythro-9-(2-hydroxy-3-nonyl)hypoxanthine)
  • 415 g of erythro-3-(2-hydroxy-3-nonyl)-4-amino-imidazole-5-carboxamide (V) (1.55 moles) are suspended in 385 ml of orthoformic acid triethylester. 220 ml of acetic acid anhydride are added with stirring. The suspension that is obtained is heated with stirring up to 100-105°C. An exothermic reaction ensues with liberation of ethanol. The liberated ethanol is separated by distillation. The temperature of the reaction mixture is increased slowly up to 130-140°C. Stirring is continued for about 3 hours, while the liberated ethanol is continuously separated by distillation. The reaction mixture is concentrated to a viscous syrup, which is stirred into a mixture of 415 ml of 30% aqueous NaOH and 1.68 liter of water. The brown solution is slightly acidified by addition of a solution of 123 ml of acetic acid in 1.5 liter of water. Erythro-9-(2-hydroxy-3-nonyl)-hypoxanthine (VI) crystallizes, is filtered by suction, washed with water and dried in vacuo at 60°C. Yield: 350 g corresponding to 81.4% of theory Melting point (after repeated recrystallization from aqueous ethanol): 200-201°C Content by titration: 99.4% Content of threo isomer: 0.9%
    • UTILIZATION OF NPT 15459 TO PRODUCE NOVEL DERIVATIVES OF NPT 15392
  • NPT 15459 and its homologues possess the ability to react with a variety of reagents which could lead to ring closure and the production of novel purine derivatives. By the judicious choice of reagents, it is possible to produce a number of 2-substituted derivatives of NPT 15392 and its homologues that could not be produced by other means. The scheme provided in the following diagram illustrates a number of such examples.
    Figure imgb0009
    erythro-2-amino-g-(2-hydroxy-3-nouyl)-hypoxuathine
  • In the reaction scheme just set forth R1 is the group
    Figure imgb0010
  • The 2,6-dichloro-purine compound in the above scheme can be converted to the 2-chloro hypoxanthine using conventional procedures, e.g. by refluxing with sodium hydroxide in the manner shown in Simon U.S. patent 4,221,909 Method D. The latter compound can then be converted to the corresponding 2-amino-hypoxanthine by reacting with methanolic ammonia in a manner analogous to that shown in Simon U.S. patent 4,221,909 Method B.
  • Compounds of formula (3) where R is methyl can be made by reacting NPT 15459 or its homologues with ethyl orthcacetate rather than ethyl orthoformate. Compounds of formula (3) where R is ethyl can be made in similar manner by reacting NPT 15459 with ethyl orthopropionate.
  • The immunomodulating activity of NPT 15459 was determined. The results are set forth below in Tables 1 and 2.
  • In Table 1 the effect of NPT 15459 on con A Induced Proliferation is described. The procedure is described in Simon U.S. patent 4,221,909, column 24, line 12 to column 25, line 10.
  • In Table 1 the effect of NPT 15459 on LPS Induced Proliferation is described.
  • In Table 2 the SRBC Induced Antibody Formation procedure employed was that shown in Simon EPO application 0036077 page 46.
    Figure imgb0011
    Figure imgb0012
    • Formulations
  • The compounds of the present invention can be fed to a mammal at a dosage of 1-1000 mg/kg of body weight and could be anticipated to be active at levels as low as 0.0005 mg/kg.
  • It is anticipated they may be administered in tablet or capsule form to humans and where solubility permits in the form of an aqueous syrup, or as solutions in oil, or where insoluble as a supension. Typical pharmaceutical formulations are described below:
    Figure imgb0013
     Suspension
  • Aqueous suspensions can be made with a number of suspending agents incorporated with the active drug substances. Included as suspending agents are such substances as sodium carboxymethylcellulose, Na alginate gum, tragacanth, Avicel RC-591 (microcellulose), methylcellulose, Veegum, Xanthan gum. In addition to a suspending agent such substances as sweetners, flavors, colorants, preservatives, protective colloids, and dispersants may be added.
    • Syrup Formulation
  • Figure imgb0014
     Tablet Formulation
    Figure imgb0015

Claims (19)

1. A compound having one of the formulae
Figure imgb0016
Figure imgb0017
or
Figure imgb0018
 where R is a lower alkyl, chlorine, or bromine and n is an integer from 1 to 5.
2. A compound according to claim 1 having formula (1).
3. A compound according to claim 1 having formula (2)..
4. A compound according to claim 1 having formula (3).
5. A compound according to claim 4 where R is lower alkyl.
6. A compound according to claim 4 wherein R is chlorine or bromine.
7. A method of preparing a compound of claim 1 having formula (1) comprising reacting 2-amino-2-cyano-acetamine with an equimolar amount of a lower alkyl orthoformate to form a compound having the formula
Figure imgb0019
where R2 is lower alkyl and reacting this compound with an equimolar amount of erythro
Figure imgb0020
. 8. A process according to claim 7 carried out in the presence of acetonitrile as a solvent and pyridine as a catalyst.
9. A process of preparing a compound of the formula
Figure imgb0021
comprising reacting a compound of formula (1) of claim 1 with an equimolar amount of a lower alkyl orthoformate in the presence of acetic anhydride.
10. A process according to claim 9 comprising removing the alcohol formed in the reaction and adding alkali after removing the alcohol to neutralize the acetic anhydride.
ll. A process of preparing a compound having the formula
Figure imgb0022
 comprising reacting a compound of formula (1) of claim 1 with an equimolar amount of cyanogen bromide.
12. A process of preparing a compound having the formula
Figure imgb0023
comprising reacting a compound of formula (1) of claim 1 with
Figure imgb0024
where X- is the anion of an acid.
13. A process of preparing a compound of the formula (4)
Figure imgb0025
 comprising reacting a compound of formula (1) of claim 1 with an equimolar amount of phosgene.
14. A process according to claim 13 including the additional step of replacing the two ring attached oxygen atoms with chlorine or bromine comprising reaction 1 mole of the compound of formula (4) with 2 moles of POCl3 or POBr3.
15. A composition comprising a compound according to any one of Claims 1 to 6 and a pharmaceutical carrier.
16. A composition according to Claim 15 in unit dosage form..
17. A compound according to any one of Claims 1 to 6 for use as an immunomodulator or an immunopotentiator.
18. Use of a compound according to Claim 1 having formula (1) for preparing erythro-9-(2-hydroxy-3-nonyl) hypoxanthine and its homologues, or for preparing a compound of formula (2) or (3).
EP83302986A 1983-05-24 1983-05-24 Process for preparing imidazole compounds Expired - Lifetime EP0126813B1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
HU85312A HUT36464A (en) 1983-05-24 1983-01-31 Process for producing erythro-4-amino-3-/2-hydroxy-3-alkyl/-imidazol-5-carboxamide
EP83302986A EP0126813B1 (en) 1983-05-24 1983-05-24 Process for preparing imidazole compounds
DE8383302986T DE3382080D1 (en) 1983-05-24 1983-05-24 METHOD FOR PRODUCING IMIDAZOLE COMPOUNDS.
AT83302986T ATE59639T1 (en) 1983-05-24 1983-05-24 PROCESS FOR THE PREPARATION OF IMIDAZOLE COMPOUNDS.

Applications Claiming Priority (1)

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EP83302986A EP0126813B1 (en) 1983-05-24 1983-05-24 Process for preparing imidazole compounds

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EP0126813A1 true EP0126813A1 (en) 1984-12-05
EP0126813B1 EP0126813B1 (en) 1991-01-02

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AT (1) ATE59639T1 (en)
DE (1) DE3382080D1 (en)
HU (1) HUT36464A (en)

Cited By (2)

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Publication number Priority date Publication date Assignee Title
GR900100212A (en) * 1989-03-20 1990-07-31 Gea Farmaceutisk Fabrik As A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process
CN1318029C (en) * 1995-07-21 2007-05-30 巧妙疗法股份有限公司 Use of aminoimidazole carboxamide and 5-amino or substituted amino 1,2,3-triazole salt in preparation of pharmaceutical composition for treating and preventing tumors

Citations (4)

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US4221909A (en) * 1978-09-15 1980-09-09 Sloan-Kettering Institute For Cancer Research P-Acetamidobenzoic acid salts of 9-(hydroxyalkyl) purines
EP0036077A2 (en) * 1980-03-14 1981-09-23 Newport Pharmaceuticals International, Inc. Esters of hydroxylalkyl-purines, processes for preparing them and therapeutical composition containing these esters as active ingredients
EP0066909A2 (en) * 1981-05-15 1982-12-15 FISONS plc Imidazole derivatives, pharmaceutical compositions containing them and processes for their production
EP0072027A1 (en) * 1981-08-11 1983-02-16 The Wellcome Foundation Limited Antiviral compounds

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IL64501A (en) * 1980-12-22 1985-07-31 Astra Laekemedel Ab 9-substituted 4-hydroxybutyl guanine derivatives,their preparation and antiviral use

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US4221909A (en) * 1978-09-15 1980-09-09 Sloan-Kettering Institute For Cancer Research P-Acetamidobenzoic acid salts of 9-(hydroxyalkyl) purines
EP0036077A2 (en) * 1980-03-14 1981-09-23 Newport Pharmaceuticals International, Inc. Esters of hydroxylalkyl-purines, processes for preparing them and therapeutical composition containing these esters as active ingredients
EP0066909A2 (en) * 1981-05-15 1982-12-15 FISONS plc Imidazole derivatives, pharmaceutical compositions containing them and processes for their production
EP0072027A1 (en) * 1981-08-11 1983-02-16 The Wellcome Foundation Limited Antiviral compounds

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Title
JOURNAL OF THE CHEMICAL SOCIETY. PERKIN I., Nr. 17, 1976 W.F. KEIR et al. "Amidinoacetamides in the synthesis of pyrimidines, imidazoles and purines", pages 1847-1852 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR900100212A (en) * 1989-03-20 1990-07-31 Gea Farmaceutisk Fabrik As A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process
WO1990011283A1 (en) * 1989-03-20 1990-10-04 A/S Gea Farmaceutisk Fabrik A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process
US5223619A (en) * 1989-03-20 1993-06-29 A/S Gea Farmaceutisk Fabrik Process for the preparation of 9-substituted guanine derivatives
HRP920907A2 (en) * 1989-03-20 1994-04-30 A/S Gea Farmaceutisk Fabrik A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process
CN1318029C (en) * 1995-07-21 2007-05-30 巧妙疗法股份有限公司 Use of aminoimidazole carboxamide and 5-amino or substituted amino 1,2,3-triazole salt in preparation of pharmaceutical composition for treating and preventing tumors

Also Published As

Publication number Publication date
EP0126813B1 (en) 1991-01-02
ATE59639T1 (en) 1991-01-15
DE3382080D1 (en) 1991-02-07
HUT36464A (en) 1985-09-30

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